Transient Receptor Potential A1 (herein, “TRPA1”) is a non-selective cation channel related to pain sensation in humans. TRPA1 is found in sensory neurons and functions as a signal transduction receptor linking inflammation to pain. Activation of TRPA1 is believed to cause pain by inducing firing of nociceptive neurons and driving central sensitization in the spinal cord. TRPA1 stimulation can also increase firing of sensory neurons, leading to the release of pro-inflammatory neuropeptides such as NK-A, substance P and CGRP (which induce vasodilation and help recruit immune cells). A variety of endogenous reactive compounds produced during inflammation activate TRPA1 (including 4-hydroxynonenal released during liposome peroxidation; cyclopentane prostaglandins synthesized by COX enzymes; hydrogen peroxide produced by oxidative stress). Activation of TRPA1 also sensitizes TRPA1 to cold. Furthermore, a gain-of-function mutation in TRPA1 causes familial episodic pain syndrome; patients suffering from this condition have episodic pain that may be triggered by cold. Thus, TRPA1 is considered to play a role in pain related to nerve damage, cold allodynia, and inflammatory pain.
Compounds that inhibit the TRPA1 ion channel can be useful, for example, in treating conditions ameliorated, eliminated or prevented by inhibition of the TRPA1 ion channel. For example, pharmaceutical compositions that inhibit TRPA1 can be used to treat pain. Inhibition of TRPA1 (e.g., by genetic ablation and chemical antagonism) has been shown to result in reduced pain behavior in mice and rats. Knockout mice lacking functional TRPA1 have diminished nociceptive responses to TRPA1 activators (including AITC, formalin, acrolein, 4-hydroxynonenal) and, in addition, have greatly reduced thermal and mechanical hypersensitivity in response to the inflammatory mediator bradykinin (e.g., Kwan, K. Y. et al. Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006, 124, 1269-1282). In animal pain models, down regulation of TRPA1 expression by gene specific antisenses prevented and reversed cold hyperalgesia induced by inflammation and nerve injury (See, e.g., Obata, K. et al., Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, S. E. et al., Nature 2004, 427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200, 112-123). TRPA1 inhibitor compounds are effective in a variety of rodent pain models. TRPA1 inhibitors have been shown to reduce mechanical hypersensitivity and cold allodynia following inflammation induced by Complete Freund's Adjuvant (without altering normal cold sensation in naïve animals) and also to improve function in the rat mono-iodoacetate osteoarthritis model. Materazzi, S et al., European Journal of Physiology 2012, 463(4):561-9; Wei H et al., Anesthesiology 2012, 117(1):137-48; Koivisto, A et al., Pharmacol Res. 2012, 65(1):149-58. TRPA1 inhibitor compounds have demonstrated reduced pain behavior in rodents injected with AITC (mustard oil), formalin, cinnamaldehyde, acrolein, and other TRPA1 activators.
A compound for inhibiting the TRPA1 ion channel is disclosed in PCT/US2009/069146 and published as WO2010/075353A1 on Jul. 1, 2010:
However, while Comparative Compound 1 is disclosed as an inhibitor of the TRPA1 ion channel, the administration of Comparative Compound 1 was later found to elevate the serum biomarkers of hepatotoxicity in certain animal studies (e.g., as disclosed in Example 5 herein).
Another compound for inhibiting the TRPA1 ion channel is disclosed in U.S. patent application No. 61/521,705 filed on Aug. 9, 2011:
While Comparative Compound 2 is an inhibitor of the TRPA1 ion channel that did not elevate the serum biomarkers of hepatotoxicity in the animal studies (as disclosed in Example 5 herein), Comparative Compound 2 has undesirably low aqueous solubility for formulation in intravenous administration (see data in Example 2 herein).
Accordingly, there remains an unmet medical need for novel compounds with greater aqueous solubility than Comparative Compound 2 (e.g., use in intravenous pharmaceutical compositions) that are therapeutically effective in the treatment of pain, respiratory conditions, and/or the inhibition of the TRPA1 ion channel, without producing serum biomarkers of hepatotoxicity observed when administering the Comparative Compound 1 (e.g., in the method of Example 5 disclosed herein). Such novel compounds preferably inhibit the TRPA1 ion channel in vivo, without producing serum biomarkers of hepatotoxicity.